Alzheimer's disease (AD) is the major cause of dementia in the elderly. The central pathogenetic step in AD involves metabolism of the beta- amyloid precursor protein (APP), resulting in brain deposition of a cleavage product, the Abeta peptide. There are genetic forms of AD but in the majority of cases, termed sporadic AD, the cause of Abeta deposition is not known. It is hypothesized that Abeta deposition in these cases results from the loss of cortical cholinergic afferents, which is known to occur early in the course of AD and also in normal aging. Cell culture work suggests that cholinergic neurotransmission shifts APP metabolism into a non-amyloidogenic pathway and therefore protects against Abeta accumulation. Supporting this concept, it has been found that immunotoxin-induced cortical cholinergic denervation results in cerebral Abeta deposition in rabbits. The proposed studies would exploit this animal model, which uses a monoclonal antibody against the p75 neurotrophin receptor, coupled to saporin, a toxin, to specifically lesion the neurons of the nucleus basalis of Meynert, which are the source of the cortical cholinergic innervation. Specific Aim #1 would determine the time course and tissue distribution of Abeta appearance and deposition. Specific Aim #2 would determine to what extent Abeta deposition is specifically dependent on cholinergic mechanisms. Control, non- cholinergic denervating lesions will be assessed for induction of Abeta deposition. These will include immunotoxin-induced cortical noradrenergic denervation and ibotenic acid-induced thalamocortical denervation. Cholinergic therapy, using both physostigmine, a acetylcholinesterase inhibitor, and xanomeline, a muscarinic agonist, will be given to attempt to reverse or prevent Abeta deposition. Specific Aim #3 will determine whether the cortical vasculature is innervated by cholinergic fibers and whether that innervating is lost in the animal model or in AD. This could lead to impaired cerebral vasoregulation and increased susceptibility to ischemia, further compromising cortical function in AD.